Investigation of potential artefactual changes in measurements of impedance changes during evoked activity: implications to electrical impedance tomography of brain function.

Electrical impedance tomography (EIT) could provide images of fast neural activity in the adult human brain with a resolution of 1 ms and 1 mm by imaging impedance changes which occur as ion channels open during neuronal depolarization. The largest changes occur at dc and decrease rapidly over 100 Hz. Evoked potentials occur in this bandwidth and may cause artefactual apparent impedance changes if altered by the impedance measuring current. These were characterized during the compound action potential in the walking leg nerves of Cancer pagurus, placed on Ag/AgCl hook electrodes, to identify how to avoid artefactual changes during brain EIT. Artefact-free impedance changes (δZ) decreased with frequency from -0.045 ± 0.01% at 225 Hz to -0.02 ± 0.01% at 1025 Hz (mean ± 1 SD, n = 24 in 12 nerves) which matched changes predicted by a finite element model. Artefactual δZ reached c.300% and 50% of the genuine membrane impedance change at 225 Hz and 600 Hz respectively but decreased with frequency of the applied current and was negligible above 1 kHz. The proportional amplitude (δZ (%)) of the artefact did not vary significantly with the amplitude of injected current of 5-20 µA pp. but decreased significantly from -0.09 ± 0.024 to -0.03 ± 0.023% with phase of 0 to 45°. For fast neural EIT of evoked activity in the brain, artefacts may arise with applied current of >10 µA. Independence of δZ with respect to phase but not the amplitude of applied current controls for them; they can be minimized by randomizing the phase of the applied measuring current and excluded by recording at >1 kHz

Simplifying the hardware requirements for fast neural EIT of peripheral nerves

OBJECTIVE: The main objective of this study was to assess the feasibility of lowering the hardware requirements for fast neural EIT in order to support the distribution of this technique. Specifically, the feasibility of replacing the commercial modules present in the existing high-end setup with compact and cheap customized circuitry was assessed. APPROACH: Nerve EIT imaging was performed on rat sciatic nerves with both our standard ScouseTom setup and a customized version in which commercial benchtop current sources were replaced by custom circuitry. Electrophysiological data and images collected in the same experimental conditions with the two setups were compared. Data from the customized setup was subject to a down-sampling analysis to simulate the use of a recording module with lower specifications. MAIN RESULTS: Compound action potentials (573±287µV and 487±279µV, p=0.28) and impedance changes (36±14µV and 31±16µV, p=0.49) did not differ significantly when measured using commercial high-end current sources or our custom circuitry, respectively. Images reconstructed from both setups showed neglibile (<1voxel, i.e. 40µm) difference in peak location and a high degree of correlation (R2=0.97). When down-sampling from 24 to 16 bits ADC resolution and from 100KHz to 50KHz sampling frequency, signal-to-noise ratio showed acceptable decrease (<-20%), and no meaningful image quality loss was detected (peak location difference <1voxel, pixel-by-pixel correlation R2=0.99). SIGNIFICANCE: The technology developed for this study greatly reduces the cost and size of a fast neural EIT setup without impacting quality and thus promotes the adoption of this technique by the neuroscience research community

Imaging fast electrical activity in the brain with electrical impedance tomography.

Imaging of neuronal depolarization in the brain is a major goal in neuroscience, but no technique currently exists that could image neural activity over milliseconds throughout the whole brain. Electrical impedance tomography (EIT) is an emerging medical imaging technique which can produce tomographic images of impedance changes with non-invasive surface electrodes. We report EIT imaging of impedance changes in rat somatosensory cerebral cortex with a resolution of 2ms and <200μm during evoked potentials using epicortical arrays with 30 electrodes. Images were validated with local field potential recordings and current source-sink density analysis. Our results demonstrate that EIT can image neural activity in a volume 7×5×2mm in somatosensory cerebral cortex with reduced invasiveness, greater resolution and imaging volume than other methods. Modeling indicates similar resolutions are feasible throughout the entire brain so this technique, uniquely, has the potential to image functional connectivity of cortical and subcortical structures

Optimization of the electrode drive pattern for imaging fascicular compound action potentials in peripheral nerve with fast neural electrical impedance tomography (EIT)

OBJECTIVE: The main objective of this study was to investigate which injection pattern led to the best imaging of fascicular compound activity in fast neural EIT of peripheral nerve using an external cylindrical 2x14-electrodes cuff. Specifically, the study addressed the identification of the optimal injection pattern and of the optimal region of the reconstructed volume to image fascicles. APPROACH: The effect of three different measurement protocol features (transversal/longitudinal injection, drive electrode spacing, referencing configuration) over imaging was investigated in simulation with the use of realistic impedance changes and noise levels. Image-based metrics were employed to evaluate the quality of the reconstructions over the reconstruction domain. The optimal electrode addressing protocol suggested by the simulations was validated in vivo on the tibial and peroneal fascicles of rat sciatic peripheral nerves (N=3) against MicroCT reference images. MAIN RESULTS: Injecting current transversally, with spacing of ≥4 electrodes apart (≥100°) and single-ring referencing of measurements, led to the best overall localization when reconstructing on the edge of the electrode array closest to the reference. Longitudinal injection protocols led to a higher SNR of the reconstructed image but poorer localization. All in vivo EIT recordings had statistically significant impedance variations (p<0.05). Overall, fascicle center-of-mass (CoM) localization error was estimated at 141±56µm (-26±94µm and 5±29° in radial coordinates). Significant difference was found (p<0.05) between mean angular location of the tibial and peroneal CoMs. SIGNIFICANCE: This study gives the reader recommendations for performing fast neural EIT of fascicular compound activity using the most effective protocol features

Effect of dispersion in nerve on compound action potential and impedance change: a modelling study

Objective: Electrical impedance tomography (EIT) is capable of imaging fast compound electrical activity (Compound Action Potentials, or CAPs) inside peripheral nerves. The ability of EIT to detect impedance changes (dZ) which arise from the opening of ion channels during the CAP is limited by the dispersion with distance from the site of onset, as fibres have differing conduction velocities. The effect is largest for autonomic nerves mainly formed of slower conducting unmyelinated fibres where signals cannot be recorded more than a few cm away from the stimulation. However, as CAPs are biphasic, monophasic dZ are expected to be detectable further than them; testing this hypothesis was the main objective of this study. Approach: An anatomically accurate FEM model and simplified statistical models of 50-fibre Hodgkin-Huxley and C-nociceptor nerves were developed with normally distributed conduction velocities; the statistical models were extended to realistic nerves. Results: 50- fibre models showed that dZ could persist further than biphasic CAPs, as these then cancelled. For realistic nerves consisting of Aα or Aβ fibres, significant dZ could be detected at 50-cm from the onset site with signal-to-noise ratios (SNR, mean ± s.d.) of 2.7±0.2 and 1.8±0.1 respectively; Aδ and rat sciatic nerve – at 20 cm (1.6±0.03 and 1.6±0.06), rat vagus – at 10 cm (1.6±0.05); C fibres – at 1-2 cm (2.4±0.02). Significance: This study provides a basis for determining the distance over which EIT may be used to image fascicular activity in electroceuticals and suggests dZ will persist further than CAPs if biphasic

Can ionic concentration changes due to mechanical deformation be responsible for the neurostimulation caused by focused ultrasound? a simulation study

Objective Ultrasound stimulation is an emerging neuromodulation technique, for which the exact mechanism of action is still unknown. Despite the number of hypotheses such as mechanosensitive ion channels and intermembrane cavitation, they fail to explain all of the observed experimental effects. Here we are investigating the ionic concentration change as a prime mechanism for the neurostimulation by the ultrasound. Approach We derive the direct analytical relationship between the mechanical deformations in the tissue and the electric boundary conditions for the cable theory equations and solve them for two types of neuronal axon models: Hodgkin-Huxley and C-fibre. We detect the activation thresholds for a variety of ultrasound stimulation cases including continuous and pulsed ultrasound and estimate the mechanical deformations required for reaching the thresholds and generating action potentials. Main results We note that the proposed mechanism strongly depends on the mechanical properties of the neural tissues, which at the moment cannot be located in literature with the required certainty. We conclude that given certain common linear assumptions, this mechanism alone cannot cause significant effects and be responsible for neurostimulation. However, we also conclude that if the lower estimation of mechanical properties of neural tissues in literature is true, or if the normal cavitation occurs during the ultrasound stimulation, the proposed mechanism can be a prime cause for the generation of action potentials. Significance The approach allows prediction and modelling of most observed experimental effects, including the probabilistic ones, without the need for any extra physical effects or additional parameters

Simulation of impedance changes with a FEM model of a myelinated nerve fibre

Objective: Fast neural Electrical Impedance Tomography (EIT) is a method which permits imaging of neuronal activity in nerves by measuring the associated impedance changes (dZ). Due to the small magnitudes of dZ signals, EIT parameters require optimization, which can be done using in silico modelling: apart from predicting the best parameters for imaging, it can also help to validate experimental data and explain the nature of the observed dZ. This has previously been completed for unmyelinated fibres, but an extension to myelinated fibres is required for the development of a full nerve model which could aid imaging neuronal traffic at the fascicular level and optimise neuromodulation of the supplied internal organs to treat various diseases. Methods: An active FEM model of a myelinated fibre coupled with external space was developed. A spatial dimension was added to the experimentally validated space-clamped model of a human sensory fibre using the double cable paradigm. Electrical parameters of the model were changed so that nodal and internodal membrane potential as well as propagation velocity agreed with experimental values. Impedance changes were simulated during activity under various conditions and the optimal parameters for imaging were determined. Main Results: When using AC, dZ could be recorded only at frequencies above 4 kHz, which is supported by experimental data. Optimal bandwidths for dZ measurement were found to increase with AC frequency. Conclusion and significance: The novel fully bi-directionally coupled FEM model of a myelinated fibre was able to optimize EIT for myelinated fibres and explain the biophysical basis of the measured signals

A method for reconstructing tomographic images of evoked neural activity with electrical impedance tomography using intracranial planar arrays

A method is presented for reconstructing images of fast neural evoked activity in rat cerebral cortex recorded with electrical impedance tomography (EIT) and a 6 × 5 mm(2) epicortical planar 30 electrode array. A finite element model of the rat brain and inverse solution with Tikhonov regularization were optimized in order to improve spatial resolution and accuracy. The optimized FEM mesh had 7 M tetrahedral elements, with finer resolution (0.05 mm) near the electrodes. A novel noise-based image processing technique based on t-test significance improved depth localization accuracy from 0.5 to 0.1 mm. With the improvements, a simulated perturbation 0.5 mm in diameter could be localized in a region 4 × 5 mm(2) under the centre of the array to a depth of 1.4 mm, thus covering all six layers of the cerebral cortex with an accuracy of <0.1 mm. Simulated deep brain hippocampal or thalamic activity could be localized with an accuracy of 0.5 mm with a 256 electrode array covering the brain. Parallel studies have achieved a temporal resolution of 2 ms for imaging fast neural activity by EIT during evoked activity; this encourages the view that fast neural EIT can now resolve the propagation of depolarization-related fast impedance changes in cerebral cortex and deeper in the brain with a resolution equal or greater to the dimension of a cortical column

Investigating the safety of fast neural electrical impedance tomography in the rat brain

Objective. Electrical Impedance Tomography (EIT) can be used to image impedance changes which arise due to fast electrical activity during neuronal depolarisation and so holds therapeutic potential for improving the localisation of epileptic seizure foci in patients with treatment-resistant epilepsy to aid surgical resection of epileptogenic tissue. Prolonged cortical stimulation may, however, induce neural injury through excitotoxicity and electrochemical reactions at the tissue-electrode interface. The purpose of this work was to assess whether current levels used in fast neural EIT studies induce histologically detectable tissue damage when applied continuously to the rat cerebral cortex. Approach. A 57-electrode epicortical array was placed on one or both hemispheres of adult Sprague-Dawley rats anaesthetised with isoflurane. In an initial series of experiments, current was injected simultaneously at 10, 25, 50, 75 and 100 µA for 1 hour at 1.725 kHz through five electrodes across two epicortical arrays to provide a preliminary indication of the safety of these current levels. Since no obvious cortical damage was observed in these rats, the current level chosen for further investigation was 100 µA, the upper-bound of the range of interest. In a separate series of experiments, 100 µA was applied through a single electrode for 1 hour at 1.725 kHz to verify its safety. Following termination of stimulation, brain samples were fixed in formalin and histologically processed with Haematoxylin and Eosin (H&E) and Nissl stains. Main results. Histological analysis revealed that continuous injection of 100 µA current, equating to a current density of 354 Am-2, into the rat cortex at 1.725 kHz does not cause cortical tissue damage or any alterations to neuronal morphology. Significance. The safety of current injections during typical EIT protocols for imaging fast neural activity have been validated. The current density established to be safe for continuous application to the cortex, 354 Am-2, exceeds the present safety limit of 250 Am-2 which has been complied with to date, and thus encourages the application of more intensified fast neural EIT protocols. These findings will aid protocol design for future clinical and in vivo EIT investigations aimed at imaging fast neural activity, particularly in situations where the signal-to-noise ratio is considerably reduced

Simultaneous EIT and EEG using frequency division multiplexing

OBJECTIVE: Methods have previously been reported for simultaneous EIT and EEG recording, but these have relied on post-hoc signal processing to remove switching artefacts from the EEG signal and require dedicated hardware filters and the use of separate EEG and EIT electrodes. This work aims to demonstrate that an uncorrupted EEG signal can be collected simultaneously with EIT data by using frequency division multiplexing (FDM), and to show that the EIT data provides useful information when compared to EEG source localisation.&#13; &#13; Approach: A custom FDM EIT current source was created and evaluated in resistor phantom and neonatal head tank experiments, where a static and dynamic perturbation was imaged. EEG and EIT source localisation were compared when an EEG dipole was placed in the tank. EEG and EIT data were collected simultaneously in a human volunteer, using both a standard EEG and a Visual Evoked Potential (VEP) paradigms.&#13; &#13; Main Results: Differences in EEG and VEP collected with and without simultaneous EIT stimulation showed no significant differences in amplitude, latency or PSD (p-values \textgreater{} 0.3 in all cases). Compared with EEG source localisation, EIT reconstructions were more accurately able to reconstruct both the centre of mass and volume of a perturbation.&#13; &#13; Significance: The reported method is suitable for collecting EIT in a clinical setting, without disrupting the clinical EEG or requiring additional measurement electrodes, which lowers the barrier to entry for data collection. EIT collection can be integrated with existing clinical workflows in EEG/ECoG, with minimal disruption to the patient or clinical team